15-68208301-C-G

Variant names:

• chr15-68208301-C-G
• rs150363441
• NM_017882.3:c.775G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_017882.3(CLN6):​c.775G>C​(p.Gly259Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G259S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLN6 NM_017882.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57
• Publications: 10 publications found

Genes affected

CLN6 (HGNC:2077): (CLN6 transmembrane ER protein) This gene is one of eight which have been associated with neuronal ceroid lipofuscinoses (NCL). Also referred to as Batten disease, NCL comprises a class of autosomal recessive, neurodegenerative disorders affecting children. The genes responsible likely encode proteins involved in the degradation of post-translationally modified proteins in lysosomes. The primary defect in NCL disorders is thought to be associated with lysosomal storage function. [provided by RefSeq, Oct 2008]

CLN6 Gene-Disease associations (from GenCC):

• ceroid lipofuscinosis, neuronal, 6A

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Myriad Women’s Health, Orphanet
• ceroid lipofuscinosis, neuronal, 6B (Kufs type)

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet
• neuronal ceroid lipofuscinosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ENSG00000260007 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 7 uncertain in NM_017882.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-68208301-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 961382.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.898

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLN6	NM_017882.3	c.775G>C	p.Gly259Arg	missense_variant	Exon 7 of 7	ENST00000249806.11	NP_060352.1
CLN6	NM_001411068.1	c.871G>C	p.Gly291Arg	missense_variant	Exon 7 of 7		NP_001397997.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLN6	ENST00000249806.11	c.775G>C	p.Gly259Arg	missense_variant	Exon 7 of 7	1	NM_017882.3	ENSP00000249806.5
ENSG00000260007	ENST00000562767.2	c.84-10673G>C		intron_variant	Intron 1 of 2	3		ENSP00000456336.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ceroid lipofuscinosis, neuronal, 6A Uncertain:1

-

Strand Center for Genomics and Personalized Medicine, Strand Life Sciences Pvt Ltd

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This is a novel homozygous variant in the CLN6 gene that has not been reported in a disease context. However, two other variations affecting the codon 259 have been reported. The missense variation p.Gly259Ser was found in the homozygous state in a 3.5 year old Indian child affected with late infantile NCL [PMID:21990111]. Another homozygous variation, p.Gly259Val, was identified in a 2 year old Italian child diagnosed with NCL and characterized by ataxia, epilepsy, visual impairment and curvilinear bodies/fingerprint profiles.The variation was found to segregate within the family, was absent in 250 controls, and was thus suspected to be the causative variant [PMID:19135028]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D;D;D;.;T;T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M;.;.;.;.;.
PhyloP100		7.6
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-6.3	D;D;D;D;.;.
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;D;D;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;.;.
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.97
MutPred		0.43		.;.;.;Gain of MoRF binding (P = 0.0279);.;.;
MVP		0.98
MPC		1.1
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.91
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs150363441; hg19: chr15-68500639;